Adavosertib (AZD-1775; MK-1775)

Description: Adavosertib (also known as AZD-1775 and MK-1775) is a novel potent and selective small molecule Wee1 tyrosine kinase inhibitor with IC50 of 5.2 nM in a cell-free assay; it hinders G2 DNA damage checkpoint. MK-1775 is a small molecule inhibitor of the tyrosine kinase WEE1 with potential antineoplastic sensitizing activity. MK-1775 selectively targets and inhibits WEE1, a tyrosine kinase that phosphorylates cyclin-dependent kinase 1 (CDC2) to inactivate the CDC2/cyclin B complex. In vivo, MK-1775 potentiated the anti-tumor efficacy of 5-FU or its prodrug, capecitabine, at tolerable doses. These enhancements were well correlated with inhibition of CDC2 phosphorylation and induction of Histone H3 phosphorylation in tumors. In addition, MK-1775 also potentiated the cytotoxic effects of pemetrexed, doxorubicin, camptothecin, and mitomycin C in vitro. These studies support the rationale for testing the combination of MK-1775 with various DNA-damaging agents in cancer patients.

References: Mol Cancer Ther. 2009 Nov; 8(11):2992-3000; Cancer Biol Ther. 2010 Apr 1; 9(7):514-22.